Preparation and use of magnesium amides

ABSTRACT

The present application relates to mixed Mg/Li amides of the general formula R 1 R 2 N—Mg—NR 3 R 4 .zLiY (II) wherein R 1 , R 2 , R 3 , and R 4  are, independently, selected from H, substituted or unsubstituted aryl or heteroaryl containing one or more heteroatoms, linear, branched or cyclic, substituted or unsubstituted alkyl, alkenyl, alkynyl, or silyl derivatives thereof; and R 1  and R 2  together, or R 3  and R 4  together can be part of a cyclic or polymeric structure; and wherein at least one of R 1  and R 2  and at least one of R 3  and R 4  is other than H; Y is selected from the group consisting of F; Cl; Br; I; CN; SCN; NCO; HaIO n , wherein n=3 or 4 and Hal is selected from Ci, Br and I; NO 3 ; BF 4 ; PF 6 ; H; a carboxylate of the general formula R x CO 2 ; an alcoholate of the general formula OR x ; a thiolate of the general formula SR x ; R x P(O)O 2 ; or SCOR x ; or SCSR x ; O n SR x , wherein n=2 or 3; or NO n , wherein n=2 or 3; and a derivative thereof; wherein R X  is a substituted or unsubstituted aryl or heteroaryl containing one or more heteroatoms, linear, branched or cyclic, substituted or unsubstituted alkyl, alkenyl, alkynyl, or derivatives thereof, or H; m is O or 1; and z&gt;1; as well as a process for the preparation of the mixed Mg/Li amides and the use of these amides, e.g. as bases.

The present application relates to magnesium amides, a method for thepreparation of magnesium amides and the use of these amides.

The metalation of aromatics is one of the most useful transformations inorganic synthesis since it allows the regioselective functionalizationof various aryl derivatives.^([1]) Traditionally, strong bases such asalkyl lithium (RLi) or lithium amides (R₂NLi) have been used to performsuch deprotonations. However, these highly reactive bases display oftenundesirable side reactions due to the too high reactivity of theresulting aryl lithium compounds. Another serious limitation is the lowstability of lithium amides in THF solutions at room temperature whichrequires an in situ generation of these reagents. Furthermore, thedeprotonation of aromatics by lithium bases often requires very lowtemperatures (−78° C. to −90° C.) which complicates the scale-up ofthese reactions and the use of solvent mixtures such as THF/pentane maybe needed.

Alternative methods have been developed using magnesium amides^([2])such as compounds 1-3 or amido zincates^([3]) 4 (see Scheme 1). The lowsolubility of the magnesium amides R₂NMgCL (1) could be improved byEaton who developed the use of magnesium amides of type R₂NMgR′ (2) and(R₂N)₂Mg (3). Nevertheless, for achieving high conversions it is usuallynecessary to use a large excess of the magnesium amides (2-8equivalents), which complicates further quenching reactions withelectrophiles (up to 15 equivalents of electrophile may have to beused). Similarly, the dialkyl amino zincate 4 requires the use of 3.5-4equivalents of an electrophile in subsequent quenching reactions.

The use of these bases is thus either limited by their poor solubility,or they are not very efficient in view of the amounts of base and theamount of electrophile needed to perform the desired conversion. Theiractivity or reactivity is very low.

The use of lithium salts to increase the solubility of Grignard reagentsis known from EP 1 582 523. In this application, the main function ofthe Grignard reagents of the general formula R*(MgX)_(n).LiY disclosedtherein is to perform a halogen/magnesium exchange in either aliphaticor aromatic systems. The Grignard reagent derivatives provide a“nucleophilic carbon atom” at a magnesium-carbon-bond. By the additionof a lithium salt to the Grignard reagent, the reactivity of theGrignard reagents can be increased by forming a magnesiate intermediate.These Grignard reagents then show a higher reactivity and selectivitydue to the formation of a magnesiate intermediate.

It is an object of the present invention to provide an inexpensivemagnesium base which is highly soluble and more reactive. A furtherobject of the present invention is to provide a magnesium base showing ahigh kinetic activity and a high selectivity.

These objects are achieved by the features of the independent claims.Preferred embodiments are set forth in the dependent claims.

Surprisingly, it was found and reported in an older patent applicationpublished as EP 1810974 A1 that mixed magnesium and lithium amides oftype R¹R²N—MgX.zLiY (I) can be prepared by reacting an amine R¹R²NH witha Grignard reagent R′MgX in the presence of LiY or with R′MgX.zLiY in asolvent.

R¹, R² and R′ independently are selected from substituted orunsubstituted aryl or heteroaryl containing one or more heteroatoms,linear, branched or cyclic, substituted or unsubstituted alkyl, alkenyl,alkynyl, or derivatives thereof, and, for R¹ and R² only, the silylderivatives thereof. One of R¹ and R² may be H; or R¹ and R² togethercan be part of a cyclic or polymeric structure.

X and Y independently are selected from the group consisting of F; Cl;Br; I; CN; SCN; NCO; HalO_(n), wherein n=3 or 4 and Hal is selected fromCl, Br and I; NO₃; BF₄; PF₆; H; a carboxylate of the general formulaR^(X)CO₂; an alcoholate of the general formula OR^(X); a thiolate of thegeneral formula SR^(X); R^(X)P(O)O₂; or SCOR^(X); O_(n)SR^(X), whereinn=2 or 3; or NO_(n), wherein n=2 or 3; and a derivative thereof; whereinR^(X) is a substituted or unsubstituted aryl or heteroaryl containingone or more heteroatoms; linear, branched or cyclic, substituted orunsubstituted alkyl, alkenyl, alkynyl, or derivatives thereof; or H.

X and Y may be identical or different. In the above given context, z>0.

The amides of formula I can also be prepared in an alternative way byreacting a lithium amide of the formula R¹R²NLi with a magnesium salt ofthe form MgX₂ or Mg XY. This reaction is preferably carried out in asolvent. In order to achieve a compound of formula I, the magnesium saltand the lithium amide are reacted in approximately equimolar ratio.Thus, the ratio of lithium amide to magnesium salt is usually in therange of 1:0.8-1.2, preferably in the range of 1:0.9-1.1, and mostpreferably in the range of 1:0.95-1.05.

The amides of formula I are not part of the present invention.

Now, additionally, the inventors found that magnesium bisamides of thegeneral formula

R¹R²N—Mg—NR³R⁴ .zLiY  (II)

can be prepared. In this formula, R¹, R², R³, and R⁴ are, independently,selected from H, substituted or unsubstituted aryl or heteroarylcontaining one or more heteroatoms, linear, branched or cyclic,substituted or unsubstituted alkyl, alkenyl, alkynyl, or silylderivatives thereof; and R¹ and R² together, and/or R³ and R⁴ togethercan be part of a cyclic or polymeric structure; and wherein at least oneof R¹ and R² and at least one of R³ and R⁴ is other than H.

X and Y are, independently, selected from the group consisting of F; Cl;Br; I; CN; SCN; NCO; HalO_(n), wherein n=3 or 4 and Hal is selected fromCl, Br and I; NO₃; BF₄; PF₆; H; a carboxylate of the general formulaR^(X)CO₂; an alcoholate of the general formula OR^(X); a thiolate of thegeneral formula SR^(X); R^(X)P(O)O₂; or SCOR^(X); or SCSR^(X);O_(n)SR^(X), wherein n=2 or 3; or NO_(R), wherein n=2 or 3; and aderivative thereof; wherein R^(X) is a substituted or unsubstituted arylor heteroaryl containing one or more heteroatoms, linear, branched orcyclic, substituted or unsubstituted alkyl, alkenyl, alkynyl, orderivatives thereof, or H;

In the above given formula II, z>0. The adduct with a solvent shouldalso be encompassed by any of the compounds of formula II.

The bisamides of the general formula II can be prepared from themonoamides of formula I. When reacting R¹R²N—MgX.zLiY with R³R⁴NLi, abisamide of formula II is formed. This reaction is equivalent to areaction of a generally known Grignard reagent R′MgX in the presence ofan amine R¹R²NH, and subsequently with R³R⁴NLi. The lithium may also beadded as a lithium salt in the form LiY, especially when the Grignardreagent or the monoamide are not complexed with a lithium salt.Obviously, the reagent may also be of the form R¹R²N—MgX.zLiY, wherein alithium salt is already present with the monoamide. In this way,bisamides may be prepared, wherein the two amides are different.However, the two amides may also be the same.

In a preferred embodiment of the present invention, the two amides aredifferent, i.e. R¹R²N is not the same as R³R⁴N. The reactivity andselectivity of the mixed magnesium lithium amides strongly depends onthe one of the two amides. If both amides are identical, the differencein reactivity and selectivity can not be seen. However, if both amidesdiffer, one of the two amides is responsible for the reactivity of thecomplex compound. In such a case, one of the two amide functions may bea cheap and easily introducible amide, and the other amide function maybe selected for the good reactivity and selectivity. In a specificallypreferred embodiment of the present invention, one of the amides is TMPand the other is diisopropyl amide.

In the following description, the magnesium amides containing two amidesare referred to as bisamides, irrespective of the fact that the twoamides may also be different. In the latter case, i.e. when the twoamides are different, these magnesium amides may also be referred to asmagnesium diamides, or heteroamides. When the two amide functions areidentical, the magnesium amide may be termed as homoamide.

Alternatively, the bisamides may be prepared by reacting two lithiumamides R¹R²NLi and R³R⁴NLi with a magnesium salt MgX₂. If both lithiumamides are identical, or a magnesium monoamide is reacted with a lithiumamide of the same type, a bisamide of the general formulaMg(NR¹R²)₂.zLiY will result. For a higher solubility of the magnesiumsalt MgX₂, this salt may be prepared in situ, for example as describedbelow.

Even though X is not present in formula II, it is defined above as it isused in the preparation of compounds of formula II. X may be selectedfrom the same group as Y and may be different or identical to Y.

The bisamides of the present invention show an increased solubility anda high reactivity. Unlike Grignard reagents, which can performhalogen/magnesium exchanges, the amides of the present invention arebases which will tolerate many functional groups, especially halogensubstituents. This is due to the different nature of the nitrogenmagnesium bond present in the amides of the present application in viewof a carbon magnesium bond as in Grignard reagents. The increase inreactivity of the Grignard reagents in the presence of a lithium salt isdue to the formation of magnesiate intermediates. In contrast thereto,however, the lithium salt which is added to the amides according to thepresent application prevents the formation of aggregates. The formationof aggregates is a well known problem in the background art in relationto magnesium amides. As a consequence, the amides known so far have tobe used in high excess as they are not very reactive. As the amides ofthe present invention are not present as aggregates due to the presenceof a lithium salt, the amides are much more reactive and more solublethan the amides known so far.

Many common solvents can be used in the present invention. In principle,any solvent capable of dissolving the specific amine and the Grignardreagent used as starting materials and the resulting products. In apreferred embodiment of the present invention, the solvent is selectedfrom cyclic, linear or branched mono or polyethers, thioethers, amines,phosphines, and derivatives thereof containing one or more additionalheteroatoms selected from O, N, S and P, preferably tetrahydrofuran(THF), 2-methyltetrahydrofuran, dibutyl ether, diethyl ether,tert-butylmethyl ether, dimethoxyethane, dioxanes, preferably1,4-dioxane, triethylamine, ethyldiisopropylamine, dimethylsulfide,dibutylsulfide; cyclic amides, preferably N-methyl-2-pyrrolidone (NMP),N-ethyl-2-pyrrolidone (NEP), N-butyl-2-pyrrolidone (NBP); cyclic, linearor branched alkanes and/or alkenes wherein one or more hydrogens arereplaced by a halogen, preferably dichloromethane, 1,2-dichloroethane,CCl₄; urea derivatives, preferably N,N′-dimethylpropyleneurea (DMPU);aromatic, heteroaromatic or aliphatic hydrocarbons, preferably benzene,toluene, xylene, pyridine, pentane, cyclohexane, hexane, heptane;hexamethylphosphorus triamide (HMPA), CS₂; or combinations thereof.

The process for the preparation of amides of formula I, which is notpart of this application, is carried out by reacting an amine R¹R²NHwith a Grignard reagent R′MgX in the presence of LiY or with R′MgX.zLiYin a solvent. The materials are contacted preferably at room temperaturefor the minimum time necessary to provide the desired yield.Temperatures between 0° C. and 50° C. are preferred, however, higher orlower reaction temperatures are also suitable. The preparation of thebisamides of formula II is usually carried out at temperatures between−40° C. and 50° C., preferably in the range of −20° C. to 30° C. andmost preferred at around 0° C. A person skilled in the art will,however, be able to select a suitable temperature for the preparation ofthe amides of formula I or II by routine experimentation.

In another preferred embodiment, X and Y are independently or both Cl,Br or I, and preferably Cl.

Preferably, the preparation of a compound of formula I is achieved byiPrMgCl.LiCl^([5]). This process is particularly preferred sinceiPrMgCl.LiCl is commercially available.

Generally, any Grignard reagent can be used to prepare the mixedMg/Li-amides in the presence of any lithium salt. It is neverthelesspreferred to use a Grignard reagent the side or by-products of which caneasily be removed from the reaction mixture. The presence of a lithiumsalt accelerates the exchange reaction compared to homoleptic reagentsRMgX and R₂Mg without the use of a lithium salt.

According to a second aspect, the present invention is directed to amixed Mg/Li bisamide of the general formula R¹R²N—MgNR³R⁴.zLiY (II),wherein R¹, R², R³, R⁴, Y and z are defined as above. It is to beunderstood that the adduct of a solvent is also comprised by any ofthese formulae.

A third aspect of the present invention is directed to a solution of theamide (II) in a solvent. The solvent can be any suitable solvent capableof dissolving the amide. Especially preferred solvents are the solventslisted above for the preparation of the amides.

All aspects and features described above in relation to the first aspectshall also apply to the second and third aspect of the invention.

In a preferred embodiment of the present invention, the solvent used todissolve the mixed amides or used for the solvent adduct of the mixedamides contains a Lewis base. A Lewis base in the understanding of thepresent application is a molecule having an electron lone pair in abonding orbital. A specifically preferred Lewis base for the amides ofthe present invention is THF. Other preferred Lewis bases may beselected from 2-methyl THF, dioxane, mixtures of THF and/or 2-methyl THFwith dioxane, mixtures of pentane and/or hexane with THF and/or 2-methylTHF, and any mixture of the compounds, selected from diethylether,diisopropylether, di-n-butyl ether, cyclopentylmethyl ether, methyltert-butyl ether, THF and 2-methyl THF.

In another preferred embodiment of the present invention, the Lewis baseis present in an amount of 4-30 eq, preferably in an amount of 4.5-20eq, even more preferably in an amount of 5-15 eq, and most preferably inan amount of 5-10 eq, in relation to the amount of Mg in the amide. Withsuch a high amount of Lewis base, stable mixed amides can more easily beproduced and can be maintained without any deterioration for longertimes.

In a fourth aspect, the present invention is related to the use of mixedMg/Li amides (II). The amides of the present invention can be used toremove acidic protons. The deprotonated species can then subsequently bequenched with an electrophile. In principle it is possible to use allkinds of electrophiles that are, for example, cited in the followingreferences, but are not limited thereto:

-   a) Handbook of Grignard reagents; edited by Gary S. Silverman and    Philip E. Rakita (Chemical industries; v. 64).-   b) Grignard reagents New Developments; edited by Herman G. Richey,    Jr., 2000, John Wiley & Sons Ltd.-   c) Methoden der Organischen Chemie, Houben-Weyl, Band XIII/2a,    Metallorganische Verbindungen Be, Mg, Ca, Sr, Ba, Zn, Cd. 1973.-   d) The chemistry of the metal-carbon bond, vol 4. edited by Frank R.    Hartley. 1987, John Wiley & Sons.

The bisamides of the present invention combine a high reactivity at ahigh selectivity or tolerance towards other functional groups within amolecule. Especially, this effect can be seen with aromatic reagentssubstituted with sensitive functional groups. These aromatic, orheteroaromatics, need a highly reactive base to be deprotonated, and atthe same time, the base has to tolerate other functional groups likeesters or nitriles. Benzonitrile or benzoic acid esters are examples ofsuch compounds. These aromatic compounds can be deprotonated with commonbases like LDA, LiHMDS oder n-BuLi, however, the bases will not tolerateany other functional groups within the reagent. On the other hand,magnesium monoamides like TMPMgCl.LiCl are too unreactive to deprotonatethe aromatic reagent. As a consequence, the base has to be added in ahigh surplus, needing a surplus of the electrophile. The new bisamidesof the present invention give a solution to this problem as thesecompounds combine a high reactivity at a high selectivity.

A preferred embodiment of the present invention refers to the use ofmagnesium bisamides of the present invention for the deprotonation ofaromatics and heterocycles. Preferably, the aromatics or heterocyclesare substituted with a phosphorodiamidate, more preferably withtetramethylphosphorodiamidate. Phosphorodiamidates can be used asdirecting metalation groups (DMG) and allow a substitution pattern ofthe aromatics or heterocyles which would otherwise not be possible.

The final aspect of the invention relates to the product of the reactionof an electrophile with a substrate which has been deprotonated with areagent of the general formula II.

In relation to the bisamide of formula II, z is preferably in the rangeof from 0.01-5, more preferably, z>1, more preferably, z is in the rangefrom 1-5, more preferably from 0.5-2.5, further more preferably from 1.5to 2.5, even more preferably from 1.8 to 2.2, even further morepreferably from 1.9 to 2.1, still even more preferably from 1.95 to2.05, and most preferred about 2.

The inventors of the present invention surprisingly found that thelithium salt is most preferably used in an equal amount in relation tothe amide function of the bisamide. For the bisamides, the amount oflithium salt is thus most preferably about 2, however, a slightdeviation of this optimum value still leads to acceptable results.

The present invention is described in the following on the basis ofspecific examples. Especially, i-PrMgCl is used as Grignard reagent.However, it is to be understood that the present invention is notlimited to such examples.

Unless otherwise defined, all technical and scientific terms used hereinhave the same meaning as commonly understood by one of ordinary skill inthe art to which this invention belongs. All publications and otherreferences mentioned herein are incorporated by reference in theirentirety.

As used herein, the terms “alkyl”, “alkenyl” and “alkynyl” refer tolinear, cyclic and branched, substituted and unsubstitued C₁-C₂₀compounds. Preferred ranges for these compounds are C₁-C₁₀, preferablyC₁-C₅ (lower alkyl) and C₂-C₁₀ and preferably C₂-C₅, respectively, foralkenyl and alkynyl. The term “cycloalkyl” generally refers to linearand branched, substituted and unsubstitued C₃-C₂₀ cycloalkanes. Here,preferred ranges are C₃-C₁₅, more preferably C₃-C₈.

Whenever any of the residues R¹, R², R³ and/or R⁴ are substituted by asubstituent, the substituent may be selected by a person skilled in theart from any known substituent. A person skilled in the art will selecta possible substituent according to his knowledge and will be able toselect a substituent which will not interfere with other substituentspresent in the molecule and which will not interfere or disturb possiblereactions, especially the reactions described within this application.Possible substituents include without limitation

-   -   halogens, preferably fluorine, chlorine, bromine and iodine;    -   aliphatic, alicyclic, aromatic or heteroaromatic hydrocarbons,        especially alkanes, alkylenes, arylenes, alkylidenes,        arylidenes, heteroarylenes and heteroarylidenes;    -   carbonxylic acids including the salts thereof;    -   carboxylic acid halides;    -   aliphatic, alicyclic, aromatic or heteroaromatic carboxylilc        acid esters;    -   aldehydes;    -   aliphatic, alicyclic, aromatic or heteroaromatic ketones;    -   alcohols and alcoholates, including a hydroxyl group;    -   phenoles and phenolates;    -   aliphatic, alicyclic, aromatic or heteroaromatic ethers;    -   aliphatic, alicyclic, aromatic or heteroaromatic peroxides;    -   hydroperoxides;    -   aliphatic, alicyclic, aromatic or heteroaromatic amides or        amidines;    -   nitriles;    -   aliphatic, alicyclic, aromatic or heteroaromatic amines;    -   aliphatic, alicyclic, aromatic or heteroaromatic imines;    -   aliphatic, alicyclic, aromatic or heteroaromatic sulfides        including a thiol group;    -   sulfonic acids including the salts thereof;    -   thioles and thiolates;    -   phosphonic acids including the salts thereof;    -   phosphinic acids including the salts thereof;    -   phosphorous acids including the salts thereof;    -   phosphinous acids including the salts thereof;

The substituents may be bound to the residues R¹, R², R³ and/or R⁴ via acarbon atom, an oxygen atom, a nitrogen atom, a sulfur atom, or aphosphorus atom. The hetero atoms in any structure containing heteroatoms, as e.g. heteroarylenes or heteroaromatics, may preferably be N,O, S and P.

When R¹ and R², or R³ and R⁴ can be part of a cyclic structure, it is tobe understood that R¹ and R² together, or R³ and R⁴ together, are adivalent saturated or unsaturated, linear or branched alkyl, alkenyl oralkynyl which forms in connection with the nitrogen atom of the amide acyclic secondary amide. An example of such a cyclic amide is the amideof TMPH. Further, the residues R¹ and R², and/or R³ and R⁴ can be partof a polymeric structure. The nitrogen atom of the amide is theconnected to a polymeric backbone which may even contain more than onenitrogen atom for the formation of an amide according to the invention.

The term “aryl” as used herein refers to substituted or unsubstitutedC₄-C₂₄ aryl. By “heteroaryl”, a substituted or unsubstituted C₃-C₂₄aryl, containing one or more heteroatoms as B, O, N, S, Se, P, is meant.Preferred ranges for both are C₄-C₁₅, more preferably C₄-C₁₀ andincludes aryls and fused aryls with or without heteroatoms. A preferredring size comprises 5 or 6 ring atoms.

Mixed magnesium and lithium amides R¹R²NMgCl.LiCl (R¹ and R²=i-Pr orR¹R²N=2,2,6,6-tetramethylpiperidyl) can be prepared by reactingi-PrMgCl.LiCl^([4,5]) with diisopropylamine or2,2,6,6-tetramethylpiperidine (TMPH), respectively, in THF (−20° C.-80°C., for 0.1-48 h). The resulting Li/Mg-reagents 5a (R¹ and R²=i-Pr) and5b (R¹R²N=2,2,6,6-tetramethylpiperidyl) proved to have an excellentsolubility in THF (0.6 M and 1.2 M, respectively) as well as an improvedkinetic acidity and regioselectivity for the magnesation of variousaromatics and heterocycles.

An overview over the increased selectivity and selectivity can be seenfrom Scheme 1a below. Here, the same substrates were reacted with a monoamide and a bisamide, and the yields of the respective reactions isgiven in the scheme. The base indicated above the reaction arrow in thescheme is the corresponding amide indicated in the right column of thescheme.

The activity of the amides (I) can be shown on the basis of themagnesiation of isoquinoline. Diisopropylamido magnesiumchloride-lithium chloride 5a leads to the magnesiated isoquinoline 6after 12 h reaction time at 25° C. and by using 2 equivalents of thebase. After iodolysis, the iodoisoquinoline 7a is isolated in 88% yield(Scheme 2). Even more active is the sterically more hindered and lessaggregated 2,2,6,6-tetramethylpiperidino magnesium chloride-lithiumchloride reagent 5b. It leads to a complete magnesiation within 2 h at25° C. Remarkably, with this base only 1.1 equivalents are required toachieve a complete metalation. The resulting Grignard reagent 6 providesafter iodolysis the iodoisoquinoline 7a in 96% yield (Scheme 2 and Table1).

After the magnesation of a reagent, it can be subjected to atransmetalation. After e.g. a transmetalation with CuCN.2LiCl (20 mol%), the addition of benzoyl chloride (1.2 equiv.) provides the ketone 7bin 86% yield (entry 2 of Table 1).

The presence of an excess of magnesium amides often hampers theperformance of palladium-catalyzed cross-couplings. The inventors foundthat the Grignard reagents generated by deprotonation with 5b (1.1equiv.) such as 6 are readily transmetalated to the corresponding zincderivative (ZnCl₂ (1.1 equiv.), 0° C., 5 min.) and undergo aNegishi-cross-coupling reaction using Pd(dba)₂ (5 mol %)(dba=dibenzylideneacetone), P(2-fur)₃ (7 mol %) (fur=furyl) with ethyl4-iodobenzoate (1.2 equiv.; 50° C., 12 h) leading to the arylatedquinoline (7c) in 82% yield. This behaviour is general and3-bromoquinoline is metalated with 5b (1.1 equiv., −30° C., 0.5 h)leading to the 2-magnesiated quinoline 8 (entries 4 and 5 of Table 1).Thus, the quenching of 8 with I₂ and N,N-dimethylformamide (DMF)provides the two quinolines 9a and 9b in 96-93% yield.

Whereas the deprotonation of 2,6-dichloropyridine with i-Pr₂NMgCl.LiCl5a and lithium diisopropylamide (LDA)^([8j]) provides a 1:1 mixture of3- and 4-magnesiated 2,6-dichloro-pyridine, the use of TMPMgCl.LiCl 5bfurnishes only the 4-magnesiated pyridine 10. Its reaction with typicalelectrophiles (I₂, DMF and PhCHO) provides the expected products 11a-cin 84-93% yield (entries 6-8 of Table 1). Interestingly, metalation of3,5-dibromopyridine with LDA proceeds selectively at 4-position^([6b])while in the case of (TMPMgCl.LiCl 5b 1.1 equiv, −20° C., 0.5 h)regioselective metalation of 3,5-dibromopyridine is observed leadingafter the reaction with DMF to the pyridylaldehyde 13 in 95% yield(entry 9 of Table 1).

The magnesiation of heterocycles bearing more acidic protons^([7]) suchas thiazole, thiophene, furan, benzothiophene or benzothiazole proceedssmoothly between 0° C. and 25° C. leading to the organomagnesiumderivatives 14a-c and 16a-b. After trapping with standard electrophiles,the expected products 15a-c and 17a-b are obtained in 81-98% yield(entries 10-14 of Table 1).

The metalation of pyrimidine derivatives is a challenging problem due tothe propensity of these heterocycles to add organometallicreagents.^([8]) The inventors found that the inverse addition of thepyrimidine derivatives 18-20 to a THF solution of 5b (1.05 equiv.) at−55° C. for approx. 5 min. provides the corresponding magnesiatedderivatives 21-23 in 83-90% yields as indicated by iodolysis experimentsleading to the iodinated pyrimidines 24-26 (scheme 3).

The mixed magnesium-lithium amide 5b is also well suited for theregioselective metalation of polyfunctional aromatic systems. Thus, thereaction of 2-phenylpyridine 27 in THF at 55° C. with 5b (2.0 equiv.)for 24 h provides the Grignard reagent 28 showing a rare case where aphenyl ring is preferentially metalated compared to a pyridine ring.After iodolysis, the ortho-iodinated product 29 is obtained in 80%yield. Interestingly, the metalation of polyfunctional aromatics such asthe bromodiester 30 also succeeds using only the stoichiometric amountof base 5b (1.1 equiv.) in THF (−30° C., 0.5 h) leading regioselectivelyto the arylmagnesium species 31 which after iodolysis furnishes thepolyfunctional aromatic derivative 32 in 88% yield.

A solution of TMPMgCl.LiCl can easily be prepared in THF due to itsexcellent solubility and it is stable for more than 6 months at 25° C.The use of TMPMgCl.LiCl allows for the regioselective functionalizationof various aromatics and heteroaromatics. It gives access to newmagnesium species not readily available via a Br/Mg-exchange reactionsor by previously reported metalation procedures.

The residues R¹ and R² are not limited to organic compounds. R¹ and R²may also be silylated compounds like trimethylsilyl. The preparation ofthe bis(trimethylsilyl) amide 33 can be achieved by reactingbis(trimethylsilyl)amine with i-PrMgCl.LiCl at room temperature (seeScheme 5). This base can efficiently be used to deprotonate ketones likee.g. cyclohexanone as can be seen from Scheme 5.

The Grignard reagents can also be used to prepare a polymeric base.2,2,6,6-Tetramethyl piperidine (TMPH) is a well known base. It can beused to prepare the corresponding mixed Mg/Li amide TMPMgCl.LiCl 5b.This monomeric base is very reactive but also very expensive. Acorresponding polymeric base to TMPH is chimassorb 994, the structure ofwhich is shown in Scheme 6.

Chimassorb 994 can be used to prepare the corresponding mixed Mg/Liamide by reacting chimassorb 994 with i-PrMgCl.LiCl at room temperature(see Scheme 5). This base 34 is stable and soluble in THF before andafter deprotonation. As being a polymeric base, it can be easily removedafter completion of the reaction. Since chimassorb 994 is much cheaperthan TMP, a corresponding base can be prepared at reduced costs. Thepolymeric base 34 shows slightly lower activity than monomericTMPMgCl.LiCl but is nevertheless very effective in deprotonatingcompounds with acidic protons like isoquinoline. A corresponding exampleis shown in Scheme 7. The polymeric base can be used to deprotonatevarious substrates. For example, isoquinoline reacts at room temperaturewith the base 34 affording after quenching with iodine1-iodoisoquinoline 7a.

The above given examples show that the new mixed Mg/Li-bases of thegeneral type R¹R²NMgX.zLiY have a high kinetic activity due to thepresence of a lithium salt which breaks oligomeric aggregates ofmagnesium amides.

An example of a symmetrical bisamide reagent is (TMP)₂Mg.2LiCl 40a. Itis prepared by reacting in situ generated MgCl₂ with lithium2,2,6,6-tetramethylpiperidide (TMPLi) in THF at 0° C. for 30 minutes(see Scheme 8).

Additionally, other symmetrical bisamides can be prepared in high yieldsusing the same methodology as for the preparation of 40a. All examplesshown below (40b-40c) were prepared in >95% yield (Scheme 9) in analogyto the preparation of 40a. This also includes bisamides containing silylsubstituted amines.

Comparative metalation experiments on aromatic substrates were performedunder identical conditions with 1.1 equivalents of both (TMP)₂Mg.2LiCl(40a) and TMPMgCl.LiCl (5b). The bisamide reagent (TMP)₂Mg.2LiCl showshighly superior reactivity than TMPMgCl.LiCl and it was even able todeprotonate very weak acidic substrates.

Scheme 10 gives an overview over examples of reactions of four differentaromatic substances (41-44) with (TMP)₂Mg.2LiCl (40a) and TMPMgCl.LiCl(5b) under identical conditions. The respective yields are indicated forthe products of each of the two amides 40a and 5b. This experimentclearly shows the even superior reactivity of the bisamides in view ofthe monoamides. All reactions are carried out at room temperature (rt)being at 25° C.

Additionally, the resultant Grignard intermediates derived from(TMP)₂Mg.2LiCl show good stability and tolerance to various substrates.Furthermore, they react with different eletrophiles providing thecorresponding functionalized derivatives in good yields. Examples areshown in Table 2 below.

It could also be shown that mixed magnesium bases bearing two differentamide functions, i.e. R¹R²N and R³R⁴N being different, have improvedproperties over the corresponding symmetrical reagents bearing twoidentical amide functions. The unsymmetrical reagents 40e-40i areprepared from TMPMgCl.LiCl, i-Pr₂NMgCl.LiCl and(2-ethyl-hexyl)₂NMgCl.LiCl^([9]), respectively, and the correspondinglithium species of 1H-benzotriazole (Bt), 5,6-dimethyl-1H-benzotriazole(DMBt) and carbazole (CBZ), respectively (Scheme 11).

Especially, the base 40e provides a far higher reactivity thanTMPMgCl.LiCl (5b) and (TMP)₂Mg.2LiCl (40a) when using special directingmetalation groups (DMG). TMPMgCl.LiCl provides full metalation of 44 in90 minutes at 0° C., and reagent 40a provides full metalation in 60minutes. In contrast thereto, the use of 40e provides full metalation at0° C. in only 10 minutes. Furthermore, only 1.3 equivalents of the base40e are used in contrast to 1.5 equivalents of TMPMgCl.LiCl. Moreover,the yield of 44a is higher compared to the use of TMPMgCl.LiCl (Scheme12).

The regulating intermediates derived from (TMP)Mg(Bt).2LiCl show goodstability and tolerance to various substrates. They can be trapped withan electrophile like iodine to provide the corresponding functionalizedderivatives in good yields. Examples are shown in Table 3.

The compounds of the present invention can also be used in connectionwith a phosphorodiamidate group on an aryl or heteroaryl. This effectwill be shown in the following with theN,N,N′,N′-tetramethylphosphorodiamidate ((Me₂N)₂P(O)O—) group, but isnot limited to this specific group. As a person skilled in the art willrecognize immediately, other directing metalation groups can also beused, especially other phosphorodiamidate groups.

Ortho-directed metalation is an important method for thefunctionalization of various aromatics and heterocycles. Various DMG(directed metalation groups) have been used for achieving efficientlithiations. The DMG allow for a fast and ortho-selective metalationmainly by chelation (entropic effect). Polar DMG may furthermoretransfer electron density to the metal base and increase theirmetalating power. Recently, magnesiate bases have proven to be of greatstructural and synthetic interest for the functionalization ofaromatics.

As was shown above, mixed Li, Mg-bases like TMP₂Mg.2LiCl are highlyactive and soluble magnesium bases allowing for smooth metalations ofvarious aromatics and heterocycles with an excellent functional groupcompatibility. Surprisingly, the inventors found that the DMG N,N,N′,N′tetramethylphosphorodiamidate ((Me₂N)₂P(O)O—) is a very strong directinggroup for magnesiation an it may overrule the effect of othersubstituents present in the aromatic substrate. In contrast to directedlithiations, which have usually to be performed at −105° C. to avoidFries-type rearrangements, the magnesiation with TMP₂Mg.2LiCl takesplace (even at 0° C.) without anionic migration of thetetramethylphosphorodiamidate group. This would allow new types offunctionalization such as formal meta- or para-functionalization (Scheme13).

Thus, the inventors have found that a range of aromaticphosphorodiamidates bearing either a functional group (FG) in thepara-position (type 60) or in the meta-position (type 61) undergo anefficient magnesiation with TMP₂Mg.2LiCl (40a) leading respectively tothe products of type 62 and 63 after the addition of an electrophile.Substitution of the OP(O)(NMe₂)₂ group with a nucleophile (Nu) givesmeta, para- and para, meta-difunctionalized molecules of type 64 and 65as described below (Scheme 13 and Table 4). The magnesiation ofsubstrates 61 and 62 using TMP₂Mg.2LiCl (40a) proceeds smoothly within afew hours at 0° C. for cyano- and ester-substituted phosphorodiamidates60a and 61a (entries 1-3, 10-13).

For halogen-substituted starting materials (60b, 60c and 60d; entries4-9) as well as for the trifluoromethyl-substituted phosphorodiamidate61b (entry 14), lower temperatures (−40 to −50° C.) led to optimumresults. In general, the regioselectivity of the metalation of aromaticsis governed by a combination of electronic and/or sterical effects.However, the tetramethylphosphorodiamidate group is one of the strongestdonor in organic synthesis and activates the Mg—N bond giving to thebase an ate character (Scheme 14).

This electronic effect increases the metalation power of the base and noadditional chelation or inductive effects are necessary for achievingthe magnesiation. Normally, this phosphorodiamidate-triggeredmagnesiation preferentially occurs at the sterically less hinderedposition of the aromatic ring promoting formal meta-metalation. However,in the case of meta-substituted substrates bearing bromo, chloro andfluoro as one of the functional groups, the inventors observed that theregioselectivity of the metalation is affected by the competitivedirecting effects of these halogens. Various electrophiles such as acidchlorides, TsCN, allylic halides, aldehydes or aromatic iodides reactwith the magnesium organometallic intermediates providing the desiredproducts in 72-90% yields (Table 4). In the case of allylation andacylation reactions, the best results were obtained when thearylmagnesium species were transmetalated with ZnCl₂ (1.2 equiv) andCuCN.2LiCl (0.5-1.3 equiv) prior to the addition of the acid chloride,TsCN or the allylic halide (entries 2-4,7,8 and 12).

Similarly, Negishi cross-couplings with aryl iodides in the presence ofPd(dba)₂ (2 mol %) and P(2-fur)₃ (4 mol %) were successfully performedafter transmetalation of the Grignard-reagents with ZnCl₂ (entries 1, 5,6 and 13). A double functionalization in meta, meta′-positions has alsobeen achieved. Thus, the treatment of the nitrile 60a with TMP₂Mg.2LiCl(1.1 equiv, 0° C., 4 h) followed by a copper(I)-catalyzed reaction witht-BuCOCl provides the ketone 62a in 81% yield. By applying the samereaction sequence (metalation at −60° C. for 0.5 h), the ketone 62a wasconverted to the diketone 66a in 77% yield. Furthermore, the doublefunctionalization of the bromo- and chloro-substitutedphosphorodiamidates 60b and 60d led to the preparation of the highlyfunctionalized phosphorodiamidates 66b and 66c in good overall yields,showing the high directing power of the OP(O)(NMe₂)₂ group (Scheme 15).

The further manipulation of the functionalized aryl phosphorodiamidatesof type 62 and 63 was best achieved by converting these intermediatesinto derived fluorinated sulfonates such as nonaflates or triflates.Thus, a microwave assisted deprotection of aryl phosphorodiamidates 62band 62c with formic acid in aqueous ethanol (120° C., 30 min) providespolyfunctional phenols, which after the reaction with C₄F₉SO₂F (NaH,Et₂O, 25° C., 12 h) allowed the isolation of the correspondingnonaflates 67a and 67b in 71% yield (Scheme 4). A nickel-catalyzedcross-coupling of nonaflate 67a with the arylzinc reagent 69 affordedthe biphenyl 68a in 90% yield. On the other hand, reaction of 67b withdimethylamine-borane complex in the presence of catalytic amount ofPd(PPh₃)₄ gave the reduced derivative 68b in 94% yield. Similarly, thearyl phosphorodiamidate 63b was successfully converted to the diester68c and to the ketoester 68d in 74% and 95% yield respectively, showingthat this reaction sequence allows either efficient functionalization orremoval of the directing metalation group (Scheme 16).

In summary, this approach allows to achieve new functionalizationpattern of aromatics by performing magnesiations using the powerfulTMP₂Mg.2LiCl base (40a) combined with the phosphorodiamidate(—OP(O)(NMe₂)₂) as strong directing metalation group. This methodologyallows a general preparation of various meta-, para- and meta,meta′-polyfunctionalized aromatics which are not easily accessible byusing conventional synthetic strategies. Applications toward thesynthesis of biologically active molecules seem to be feasible with thisapproach.

As can be seen from the above given examples, the new mixed Mg/Li-basesare very effective in deprotonating organic compounds. The deprotonationcan be achieved in different solvents and can preferably be conducted attemperatures between −90° C. and 100° C. Further, due to the effectivedeprotonation reaction, the amides of the present invention preferablyonly require the use of 0.9-5 equivalents, more preferably 1-2equivalents and most preferably 1.1-1.5 equivalents per proton to bedeprotonated.

With this new type of base, which is highly soluble and the sideproducts of which do not disturb the following reactions, many newproducts may be obtained, or known reactions pathways will be moreefficient. A person skilled in the art will easily recognise the benefitof the new Mg/Li-base and will be able to use this base in a widevariety of chemical reactions.

In the following, examples are given to illustrate the presentinvention. However, these examples are given for illustrative purposesonly and are not supposed to limit the scope of the invention which isdetermined by the claims below.

Experimental Section Preparation of the reagent TMPMgCl.LiCl (5b):

A dry and argon flushed 250 mL flask, equipped with a magnetic stirrerand a septum, was charged with freshly titrated i-PrMgCl.LiCl (100 mL,1.2 M in THF, 120 mmol). 2,2,6,6-tetramethylpiperidine (TMPH) (19.8 g,126 mmol, 1.05 equiv) was added dropwise at room temperature. Thereaction mixture was stirred until gas evaluation was completed (ca. 24h) at room temperature.

Preparation of 1-iodoisoquinoline (7a)

A dry and argon flushed 10 mL flask, equipped with a magnetic stirrerand a septum, was charged with TMPMgCl.LiCl (5 mL, 1.2 M in THF, 6.0mmol). Isoquinoline (703 mg, 5.45 mmol) in THF (5 ml) was added dropwiseat room temperature. During addition, the reaction mixture became redand the metalation was complete after 2 h (as checked by GC analysis ofreaction aliquots quenched with a solution of I₂ in THF, the conversionwas more than 98%). A solution of I₂ in THF (6 ml, 1 M in THF, 6.0 mmol)was slowly added at −20° C. The reaction mixture was quenched with sat.aqueous NH₄Cl solution (10 mL). The aqueous phase was extracted withether (4×10 mL), dried with Na₂SO₄ and concentrated in vacuo. The cruderesidue was purified by filter column chromatography (CH₂Cl₂/pentane)yielding 1-iodoisoquinoline (7a; 1.33 mg, 96%) as slightly yellowcrystals (mp=74-76° C.).

The products listed in table 1 below can be produced according to thepreparation of 1-iodoisoquinoline (7a).

TABLE 1 Products obtained by the magnesiation of heterocycles withTMPMgCl•LiCl (5b) and reaction with electrophiles. Magnesium T, t YieldEntry reagent^([a]) [° C., h]^([b]) Electophile Product (%)^([c]) 1

  25,    2 I₂

96 2  6   25, PhCOCl^([d]) 7b: R = COPh 86    2 3  6   25,    2

7c: R = 4-EtO₂C₆H₄ 82 4

−30,    0.5 I₂

96 5  8 −30, DMF 9b: R = CHO 93    0.5 6

  25,    0.1 I₂

93 7 10   25, DMF 11b: R = CHO 90    0.1 8 10   25, PhCHO 11c: R =CH(OH)Ph 84    0.1 9

−25,    0.5 DMF

95 10

  25,   24 DMF

81 11 14b: X = S,   25, DMF 15b: R = CHO 90 Y = CH   24 12 14c: X = S,   0, PhCHO 15c: R = CH(OH)Ph 94 Y = N    0.1 13

  25,   24 DMF

93 14 16b: X = S,    0, I₂ 17b: R = I 98 Y = N    0.1 ^([a])Lithiumchloride and TMPH are complexed to the Grignard reagent. ^([b])Reactionconditions for the deprotonation with TMPMgCl•LiCl (5b, 1.1 equiv.).^([c])Isolated yield of analytically pure product. ^([d])Atransmetalation with CuCN•2LiCl (0.2 equiv) was performed

Preparation of (TMP)₂Mg.2LiCl (40a)

Magnesium turnings (15 mmol) were placed in an argon-flushed-Schlenkflask and THF (30 ml) was added. 1,2-Dichloroethane (16 mmol) was addeddropwise and the reaction was stirred until all magnesium was consumed,approximately 2 h. In another argon-flushed-Schlenk flask2,2,6,6-tetramethylpiperidine (TMPH) (30 mmol) and THF (20 ml) wereplaced. This solution was cooled to −40° C. and n-BuLi (30 mmol) wasadded dropwise. After the addition, the reaction mixture was warmed to0° C. and stirred at same temperature for 30 min. The MgCl₂ solution wasthen transferred via cannula into the TMPLi solution and the reactionmixture was stirred at 0° C. for 30 min, then warmed to room temperatureand stirred for an additional 1 h. The solvents were removed then invacuo followed by addition of THF while stirring until completedissolution of the salts. The fresh (TMP)₂Mg.2LiCl solution was titratedprior to use at 0° C. against benzoic acid using4-(phenylazo)-diphenylamine as indicator.Average concentration in THFwas 0.6 mol/1.

Preparation of (PIR)₂Mg.2LiCl (40b)

Prepared according to 40a from pyrrolidine (PIR) (30 mmol), n-BuLi (30mmol), magnesium turnings (15 mmol) and 1,2-dichloroethane (16 mmol) inTHF. Average concentration in THF was found to be 0.65 mol/l.

Preparation of (i-Pr)₂NMg.2LiCl (40c)

Prepared according to 40a from diisopropylamine (30 mmol), n-BuLi (30mmol), magnesium turnings (15 mmol) and 1,2-dichloroethane (16 mmol) inTHF. Average concentration in THF was found to be 0.84 mol/1.

Preparation of (HMDS)₂Mg.2LiCl (40d)

Prepared according to 40a from 1,1,1,3,3,3-hexamethyldisilazane (HMDS)(30 mmol), n-BuLi (30 mmol), magnesium turnings (15 mmol) and1,2-dichloroethane (16 mmol) in THF. Average concentration in THF wasfound to be 0.86 mol/L.

Preparation of (TMP)Mg(BT).2LiCl (40e)

Benzotriazole (Bt)(1.19 g, 10.0 mmol) was placed in a flame dried, argonflushed 50 ml Schlenk tube equipped with magnetic stirring bar andseptum. THF (10 ml) was added. The solution was cooled to −40° C. Thenn-BuLi (3.62 ml, 2.76 M in hexane, 10.0 mmol) was added drop wise. Whiteprecipitate was formed immediately. After the end of the addition theresulting suspension was stirred at −40° C. for 30 min. Then solventswere removed in vacuo followed by addition of TMPMgCl.LiCl (8.93 ml,1.12 M in THF, 10.0 mmol). After the complete dissolving of the whitesolid, THF was removed in vacuo. To the resulting brownish gel, THF wasadded while stirring until complete dissolution of the salts. The fresh(TMP)Mg(Bt).2LiCl solution was titrated at room temperature againstbenzoic acid using 4-(phenylazo)-diphenylamine as an indicator. Averageconcentration in THF was found to be 0.35 mol/1.

Preparation of (TMP)Mg(DMBt).2LiCl (40f)

Prepared according to 40e from 5,6-dimethyl-1H-benzotriazole (10 mmol),n-BuLi (10 mmol) and TMPMgCl.LiCl (10 mmol) in THF. Averageconcentration in THF was found to be 0.33 mol/l.

Preparation of (TMP)Mg(CBZ).2LiCl (40g)

Prepared according to 40e from 9H-carbazole (10 mmol), n-BuLi (10 mmol),TMPMgCl.LiCl (10 mmol) in THF. Average concentration in THF was found tobe 0.33 mol/l.

Preparation of (i-Pr₂N)Mg(Bt).2LiCl (40h)

Prepared according to 40e from benzotriazole (10 mmol), n-BuLi (10 mmol)and (i-Pr₂N)MgCl.LiCl (10 mmol) in THF. Average concentration in THF wasfound to be 0.24 mol/1.

Preparation of (2-ethyl-hexyl)₂NMg(Bt).2LiCl (40i)

Prepared according to 40e from benzotriazole (10 mmol), n-BuLi (10 mmol)and (2-ethyl-hexyl)₂NMgCl.LiCl (10 mmol) in THF. Average concentrationin THF was found to be 0.23 mol/l.

Preparation of (iPr(N)tBu)₂Mg.2LiCl (40j)

Prepared according to 40a from iso-propyl(tert-butyl)amine (30 mmol),n-BuLi (30 mmol), magnesium turnings (15 mmol) and 1,2-dichloroethane(16 mmol) in THF. Average concentration in THF was found to be 0.80mol/L.

Preparation of (iPr(N)cHex)₂Mg.2LiCl (40k)

Prepared according to 40a from iso-propyl(cyclo-hexyl)amine (30 mmol),n-BuLi (30 mmol), magnesium turnings (15 mmol) and 1,2-dichloroethane(16 mmol) in THF. Average concentration in THF was found to be 0.60mol/L

Magnesiations of functionalized arenes with (TMP)₂Mg.2LiCl Preparationof di-tert-butyl 4-iodobenzene-1,3-dioate (51a)

A dry and nitrogen-flushed 10-ml-Schlenk-flask, equipped with a magneticstirring bar and a septum, was charged with a solution of thedi-tert-butyl isophthalate (278 mg, 1 mmol) in dry THF (1 ml). Aftercooling to 0° C., a freshly prepared (TMP)₂1Mg.2LiCl solution (0.6 mol/lin THF, 1.83 ml, 1.1 mmol) was added dropwise and the reaction mixturewas stirred at the same temperature. The completion of the metalation (2h) was checked by GC-analysis of reaction aliquots quenched with asolution of I₂ in dry ether. Iodine (508 mg, 2 mmol) dissolved in dryTHF (2 ml) was then added at 0° C. and the resulting mixture warmed toroom temperature. After stirring for 1 hour, the reaction mixture wasquenched with sat. aq. Na₂S₂O₃, extracted with ether (3×20 ml) and driedover Na₂SO₄. After filtration the solvent was removed in vacuo.Purification by flash-chromatography (n-pentane/diethyl ether, 10:1)furnished compound Ma (380 mg, 94%) as a yellow oil.

The products listed in Table 2 below can be produced according to thepreparation of di-tert-butyl 4-iodobenzene-1,3-dioate (51a), using thecorresponding temperatures and reactions times as indicated in thetable.

TABLE 2 Products obtained by the magnesiation of aromatics with(TMP)₂Mg•2LiC1 and reactions with eletrophiles. Entry Substrate Temp. [°C.] Time Electrophile E⁺ Product Yield 1

25  1 h PhCOCl^(a)

93% 2 41 25  1 h p-IPhCO₂Et^(b) 41c: E = p-PhCO₂Et 82% 3

−10  1 h I₂

71% 4 53 −10  1 h PhCOCl^(a) 53b: E = COPh 52% 5

25  1 h I₂

78% 6 45 25 1 h EtCOCl^(a) 45b: E = COEt  7% 7

0  2 h I₂

 6% 8 47: X = Br −20 3 h I₂ 47a: E = I 74% 9

−20  4 h I₂

91% 10 48 −20 4 h PhCOCl^(a) 48b: E = PhCO 62% 11

0  5 h BrCl₂C₂Cl₂Br

60% 12

−40  5 h I₂

77% 13 49 −40  5 h BrCl₂C₂Cl₂Br 49b: = Br 70% 14

−40 12 h I₂

66% 15

25 2 h I₂

94% ^(a)A transmetalation with CuCN•2LiCl was performed. ^(b)Obtained bypalladium-catalyzed cross-coupling after transmetalation with ZnCl₂.

Magnesiations of functionalized arenes with (TMP)Mg(Bt).2LiClPreparation of ethyl3-{[bis(dimethylamino)phosphoryl]oxy}-2-iodobenzoate (44a)

A dry and nitrogen-flushed 25-ml Schlenk flask, equipped with a magneticstirring bar and a septum, was charged ethyl3-{[bis(dimethylamino)phosphoryl]oxy}benzoate 44 (300 mg, 1.00 mmol) indry THF (3 ml). After cooling to 0° C., a freshly prepared(TMP)Mg(Bt).2LiCl solution (4.33 ml, 0.3 M in THF, 1.3 mmol) was addeddropwise and the reaction mixture was stirred at the same temperature.The completion of the metalation (10 min) was checked by GC-analysis ofreaction aliquots quenched with a solution of I₂ in dry THF. Iodine (508mg, 2.0 mmol) dissolved in dry THF (2 ml) was then added at 0° C. andthe resulting mixture warmed to room temperature. After stirring for 1hour, the reaction mixture was quenched with sat. aq. Na₂S₂O₃, extractedwith ether (3×20 ml) and dried over Na₂SO₄. After filtration, thesolvent was removed in vacuo. Purification by flash-chromatography usingethyl acetate as eluent furnished ethyl3-{[(bis(dimethylamino)phosphoryl]oxy}-2-iodobenzoate 44a (332 mg, 78%)as a yellow oil.

The products listed in Table 3 below can be produced according to thepreparation of ethyl 3-{[b is(dimethylamino)phosphoryl]oxy}-2-iodobenzoate 44a, using thecorresponding temperatures and reactions times as indicated in thetable.

TABLE 73 Products obtained by the magnesiation of aromatics with(TMP)Mg(Bt)•2LiCl and reactions with eletrophiles. Entry Substate Temp.[° C.] Time Electrophile Product Yield 1

0  6 h I₂

69% 2 41 25  1 h I₂ 41a 67% 3

0 10 min I₂

78% 4

0 30 min I₂

73%

Preparation of the reagent TMP₂Mg.2LiCl (40a) from TMPMgCl.LiCl

In a dry argon-flushed Schlenk-tube, 2,2,6,6-tetramethylpiperidine(TMPH; 5.07 mL, 30 mmol) was dissolved in THF (30 mL). This solution wascooled to −40° C., and n-BuLi (2.4 in hexane, 12.5 mL, 30 mmol) wasadded dropwise. After the addition was complete, the reaction mixturewas warmed to 0° C. and stirred at this temperature for 30 min. Freshlytitrated TMPMgCl.LiCl (5b) (1 M in THF, 30 mL, 30 mmol) was then addeddropwise to the LiTMP-solution, the reaction mixture was stirred at 0°C. for 30 min, warmed to 25° C. and stirred for 1 h. The solvents werethen removed in vacuo without heating, affording a yellowish solid.Freshly distilled THF was slowly added under vigorous stirring, until acomplete dissolution of the salts was observed. The fresh TMP₂Mg.2LiClsolution was titrated prior to use at 0° C. with benzoic acid using4-(phenylazo)-diphenylamine as indicator. A concentration of 0.6 M inTHF was obtained.

Synthesis of 5-chloro-4′-methoxybiphen-2-ylN,N,N′,N′-tetramethyldiamidophosphate (62c)

In a dry argon-flushed Schlenk-tube the aryl phosphorodiamidate 60d(2.62 g, 8.00 mmol) was dissolved in THF (8 mL), cooled to −40° C. andTMP₂Mg.2LiCl (0.6 M in THF, 14.7 mL, 8.8 mmol) was added dropwise. Themixture was stirred at −40° C. for 1.5 h. Complete metalation wasdetected by GC-analysis of reaction aliquots which were quenched with I₂in dry THF. A solution of ZnCl₂ (1 M in THF, 9.6 mL, 9.6 mmol) was addeddropwise, and the resulting mixture stirred for 15 min. A solution ofPd(dba)₂ (88 mg, 2 mol %) and P(2-fur)₃ (72 mg, 4 mol %) in THF (8 mL)was added, followed by 4-iodoanisole (2.06 g, 8.8 mmol) and the reactionmixture was allowed to warm to room temperature. After stirring for 12h, the reaction mixture was quenched with aq. sat. NH₄Cl solution (20mL) and extracted with diethyl ether (3×50 ml). The combined organiclayers were washed with brine, dried over MgSO₄, filtered andconcentrated in vacuo. Purification by flash chromatography on silicagel (ethyl acetate) furnished 62c (2.78 g, 90% yield) as an orange oil.

TABLE 4 Products of type 62 and 63 obtained by direct magnesiation ofthe aromatic phosphoroamidates 60 and 61 with (TMP)₂Mg•2LiCl (2)followed by the reaction with electrophiles (E-X). T [° C.], Yield EntrySubstrate t [h] E-X Product [%]^(a) 1

   0,    1 p-IC₆H₄OTIPS

83^(c) 2 60a    0, TsCN 62e: E = CN 77^(b)    1 3 60a    0,CH₂═C(CH₃)CH₂Br 62f: E = CH₂═C(CH₃)CH₂ 84^(b)    1 4

−50,    7 tBuCH₂COCl

72^(b) 5

−40,    4 p-IC₆H₄CO₂Et

78^(c) 6 60c −40, m-Tol-I 62i: E = m-Tol 75^(c)    4 7 60c −40, c-C₆H₉Br62j: E = c-C₆H₉ 85^(b)    4 8

−40,    1.5 PhCOCl

85^(b) 9 60d −40, tBuCHO 62l: E = tBuC(OH) 79    1.5 10

   0,    1 (BrCl₂C)₂

80 12 61a    0, PhCOCl 63b: E = COPh 73^(b)    1 13 61a    0,p-IC₆H₄CO₂Et 63c: E = p-C₆H₄CO₂Et 78^(c)    1 14

−40,    2 I₂

88 15

   0,    0.5 (BrCl₂C)₂

76 ^(a)Isolated yield of analytically pure product. ^(b)Atransmetalation with ZnCl₂  (1.1 equiv) and CuCN•2LiCl (0.5-1.3 equiv)was performed. cObtained by a palladium-catalyzed cross-coupling aftertransmetalation with ZnCl₂  (1.1 equiv).

REFERENCES AND NOTES

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1. A reagent of the general formulaR¹R²N—Mg—NR³R⁴ .zLiY  (II) wherein R¹, R², R³, and R⁴ are,independently, selected from H, substituted or unsubstituted aryl orheteroaryl containing one or more heteroatoms, linear, branched orcyclic, substituted or unsubstituted alkyl, alkenyl, alkynyl, or silylderivatives thereof; and R¹ and R² together, or R³ and R⁴ together canbe part of a cyclic or polymeric structure; and wherein at least one ofR¹ and R² and at least one of R³ and R⁴ is other than H; Y is selectedfrom the group consisting of F; Cl; Br; I; CN; SCN; NCO; HalO_(n),wherein n=3 or 4 and Hal is selected from Cl, Br and I; NO₃; BF₄; PF₆;H; a carboxylate of the general formula R^(X)CO₂; an alcoholate of thegeneral formula OR^(X); a thiolate of the general formula SR^(X);R^(X)P(O)O₂; or SCOR^(X); or SCSR^(X); O_(n)SR^(X), wherein n=2 or 3; orNO_(R), wherein n=2 or 3; and a derivative thereof; wherein R^(X) is asubstituted or unsubstituted aryl or heteroaryl containing one or moreheteroatoms, linear, branched or cyclic, substituted or unsubstitutedalkyl, alkenyl, alkynyl, or derivatives thereof, or H; and z>1; or asadduct with a solvent.
 2. Solution of the reagent according to claim 1in a solvent.
 3. Solution according to claim 2, wherein the solvent isselected from cyclic, linear or branched mono or polyethers, thioethers,amines, phosphines, and derivatives thereof containing one or moreadditional heteroatoms selected from O, N, S and P, dibutyl ether,diethyl ether, tert-butylmethyl ether, dimethoxyethane, dioxanes,triethylamine, ethyldiisopropylamine, dimethylsulfide, dibutylsulfide;cyclic amides, cyclic, linear or branched alkanes and/or alkenes whereinone or more hydrogens are replaced by a halogen, urea derivatives,aromatic, heteroaromatic or aliphatic hydrocarbons, hexamethylphosphorustriamide (HMPA), CS₂; or combinations thereof.
 4. Solution according toclaim 3, wherein the solvent is 1,4-dioxane.
 5. Solution according toclaim 3, wherein the solvent is tetrahydrofuran (THF) or2-methyltetrahydrofuran.
 6. Solution according to claim 3, wherein thesolvent is N-methyl-2-pyrrolidone (NMP), N-ethyl-2-pyrrolidone (NEP),and/or N-butyl-2-pyrrolidone (NBP).
 7. Solution according to claim 3,wherein the solvent is N,N′-dimethylpropyleneurea (DMPU).
 8. Solutionaccording to claim 3, wherein the solvent is dichloromethane,1,2-dichloroethane, and/or CCl₄.
 9. Solution according to claim 3,wherein the solvent is benzene, toluene, xylene, pyridine, pentane,cyclohexane, hexane, and/or heptane.
 10. Use of the reagent according toclaim 1 in a reaction with an electrophile.
 11. Use of the reagentaccording to claim 1 for the deprotonation of any substrate which canform stabilized or unstabilized carbaniones.
 12. Process for thepreparation of a mixed Mg/Li amide comprising reacting in a solvent aprimary or secondary amine with a Grignard reagent in the presence of alithium salt, or with a Grignard reagent complexed with a lithium salt,or reacting in a solvent a primary or secondary lithium amide with amagnesium salt.
 13. Process for the preparation of a reagent having thegeneral formulaR¹R²N—Mg—NR³R⁴ .zLiY  (II) wherein R¹, R², R³, and R⁴ are,independently, selected from H, substituted or unsubstituted aryl orheteroaryl containing one or more heteroatoms, linear, branched orcyclic, substituted or unsubstituted alkyl, alkenyl, alkynyl, or siliconderivatives thereof; and R¹ and R² together, or R³ and R⁴ together canbe part of a cyclic or polymeric structure; and wherein at least one ofR¹ and R² and at least one of R³ and R⁴ is other than H; Y is selectedfrom the group consisting of F; Cl; Br; I; CN; SCN; NCO; HalO_(n),wherein n=3 or 4 and Hal is selected from Cl, Br and I; NO₃; BF₄; PF₆;H; a carboxylate of the general formula R^(X)CO₂; an alcoholate of thegeneral formula OR^(X); a thiolate of the general formula SR^(X);R^(X)P(O)O₂; or SCOR^(X); or SCSR^(X); O_(n)SR^(X) wherein n=2 or 3; orNO_(n) wherein n=2 or 3; and a derivative thereof; wherein Rx is asubstituted or unsubstituted aryl or heteroaryl containing one or moreheteroatoms, linear, branched or cyclic, substituted or unsubstitutedalkyl, alkenyl, alkynyl, or derivatives thereof, or H; and z>1;comprising reacting in a solvent R¹R²N—MgX or R¹R²N—MgX.zLiY withR³R⁴NLi, or reacting R¹R²NLi and R³R⁴NLi with MgX₂; and X is defined asY above.
 14. Process according to claim 13, wherein X and Y areindependently or both Cl, Br or I.
 15. Process according to claim 14,wherein X and Y are independently or both Cl.
 16. Process according toclaim 13, wherein z is in the range from 1-5.
 17. Process according toclaim 16, wherein z is in the range from 1.5-2.5.
 18. Process accordingto claim 16, wherein z is in the range from 1.8-2.2.
 19. Processaccording to claim 16, wherein z is in the range from 1.9-2.1. 20.Process according to claim 16, wherein z is in the range from 1.95-2.05.21. Process according to claim 16, wherein z is about
 2. 22. Processaccording to claim 13, wherein the Grignard reagent R′MgX.zLiY isiPrMgCl.LiCl.
 23. Process according to claim 13, wherein the solvent isselected from cyclic, linear or branched mono or polyethers, thioethers,amines, phosphines, and derivatives thereof containing one or moreadditional heteroatoms selected from O, N, S and P, dibutyl ether,diethyl ether, tert-butylmethyl ether, dimethoxyethane, dioxanes,triethylamine, ethyldiisopropylamine, dimethylsulfide, dibutylsulfide;cyclic amides; cyclic, linear or branched alkanes and/or alkenes whereinone or more hydrogens are replaced by a halogen; urea derivatives;aromatic, heteroaromatic or aliphatic hydrocarbons; hexamethylphosphorustriamide (HMPA), CS₂; or combinations thereof.
 24. Process according toclaim 13, wherein the solvent is 1,4-dioxane.
 25. Process according toclaim 13, wherein the solvent is tetrahydrofuran (THF) or2-methyltetrahydrofuran.
 26. Process according to claim 13, wherein thesolvent is N-methyl-2-pyrrolidone (NMP), N-ethyl-2-pyrrolidone (NEP),and/or N-butyl-2-pyrrolidone (NBP).
 27. Process according to claim 13,wherein the solvent is N,N′-dimethylpropyleneurea (DMPU).
 28. Processaccording to claim 13, wherein the solvent is benzene, toluene, xylene,pyridine, pentane, cyclohexane, hexane, and/or heptane.
 29. Processaccording to claim 13, wherein the solvent is dichloromethane,1,2-dichloroethane, and/or CCl₄.